Background: Second-generation antipsychotic drugs (SGAs) are essential in the treatment of psychotic disorders, but are well-known for inducing substantial weight gain and obesity. Critically, weight gain may reduce life expectancy for up to 20-30 years in patients with psychotic disorders, and prognostic biomarkers are generally lacking. The dorsal striatum, rich in dopamine D2 receptors which are antagonized by antipsychotic medications, plays a key role in the human reward system and in appetite regulation, suggesting that altered dopamine activity in the striatal reward circuitry may be responsible for increased food craving and resultant weight gain. Methods: Here, we measured striatal volume and striatal resting state functional connectivity at baseline, and weight gain over the course of 12 weeks of antipsychotic treatment in 81 patients with early-phase psychosis. We also included a sample of 58 healthy controls. Weight measurements were completed at baseline, and then weekly for 4 weeks, and every 2 weeks until week 12. We used linear mixed models to compute individual weight gain trajectories. Striatal volume and whole-brain striatal connectivity were then calculated for each subject, and used to assess the relationship between striatal structure and function and individual weight gain in multiple regression models. Outcomes: Patients had similar baseline weights and body mass indices (BMI) compared to healthy controls. There was no evidence that prior drug exposure or duration of untreated psychosis correlated with baseline BMI. Higher left putamen volume and lower frontopolar connectivity predicted magnitude of weight gain in patients, and these effects multiplied when the structure-function interaction was considered. Interpretation: These results provide evidence for a synergistic effect of striatal structure and function on antipsychotics-induced weight gain. Lower fronto-striatal connectivity, implicated in less optimal long-term decision making, was associated with more weight gain, and this relationship was stronger for higher compared to lower left putamen volumes.

Striatal volume and functional connectivity predict weight gain in early-phase psychosis